Neuron-specific mitochondrial oxidative stress results in epilepsy, glucose dysregulation and a striking astrocyte response
Ruth Fulton, Jennifer N. Pearson-Smith, Christopher Huynh, Timothy Fabisiak, Liping Liang, Stefanos Aivazidis, Brigit High, Georgia Buscaglia, Timothy Corrigan, Robert Valdez, Takahiko Shimizu, Manisha N. Patel
Abstract
Mitochondrial superoxide (O2−) production is implicated in aging, neurodegenerative disease, and most recently epilepsy. Yet the specific contribution of neuronal O2− to these phenomena is unclear. Here, we selectively deleted superoxide dismutase-2 (SOD2) in neuronal basic helix-loop-helix transcription factor (NEX)-expressing cells restricting deletion to a subset of excitatory principle neurons primarily in the forebrain (cortex and hippocampus). This resulted in nSOD2 KO mice that lived into adulthood (2–3 months) with epilepsy, selective loss of neurons, metabolic rewiring and a marked mitohormetic gene response. Surprisingly, expression of an astrocytic gene, glial fibrillary acidic protein (GFAP) was significantly increased relative to WT. Further studies in rat primary neuron-glial cultures showed that increased mitochondrial O2−, specifically in neurons, was sufficient to upregulate GFAP. These results suggest that neuron-specific mitochondrial O2− is sufficient to drive a complex and catastrophic epileptic phenotype and highlights the ability of SOD2 to act in a cell-nonautonomous manner to influence an astrocytic response.